DESCRIPTION (Applicant's abstract): Pulmonary edema (too much fluid in the lungs) is one of the most common and serious complications of heart failure. The edema results from increased pulmonary capillary pressure (Pc) when the left cardiac ventricle fails. The high pressure pushes fluid out of the capillaries faster that the lymphatic vessels can drain the fluid from the lungs. The excess fluid that can not be removed by the lymphatics accumulates within the lung as edema. Studies with animals have shown this phase of edema formation is completed within 4 hours. This application is to investigate the hypothesis that there is a second, previously unknown and uninvestigated mechanism of pulmonary edema caused by elevated Pc. According to this hypothesis, the amount of connective tissue in the lung is increased when Pc is elevated for several days. The connective tissue, due to its potential to absorb fluid, pulls fluid from the capillaries and into the lung tissue. Because it may take several days for excess connective tissue to accumulate, the associated fluid will be called "late phase edema." The first specific aim is to test if lung connective tissue is increased and late phase edema occurs in a sheep model of elevated Pc. Lung connective tissue and the amount of edema fluid will be compared for sheep with Pc elevated 7 days vs sheep in which Pc is elevated only 4 hours. Limited lung lymphatic drainage may contribute to the pulmonary edema in some types of heart failure. For the second aim the effect of limited lymph flow will be tested by comparing the increase in lung connective tissue and late phase edema in sheep with limited lymph flow to lung connective tissue and late phase edema in sheep in which lymph flow is not limited. The third aim is to test the hypothesis the increase in connective tissue and lung fluid will decrease lung compliance and increase lung resistance to airflow. Specific aim 4 is to test the hypothesis the increase in lung connective tissue is a response to the early phase fluid that accumulates in the first 4 hours of elevated Pc. Low plasma protein osmotic pressure will be used to cause early phase edema in sheep without increased Pc. After 7 days, the lungs will be analyzed to determine if connective tissue content and lung fluid have increased. These studies will test a previously unknown mechanism for the pulmonary edema associated with heart failure.